Early T-Cell Precursor Acute Lymphoblastic Leukemia: Diagnosis, Updates in Molecular Pathogenesis, Management, and Novel Therapies.

Chun-Fung Sin,Pui-Hei Marcus Man

doi:10.3389/fonc.2021.750789

Abstract

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T lymphoblastic leukemia (T-ALL) identified in 2009, due to its unique immunophenotypic and genomic profile. The outcome of patients was poor in earlier studies, and they were prone to have induction failure, with more frequent relapse/refractory disease. Recent advances had been made in discoveries of genetic aberrations and molecular pathogenesis of ETP-ALL. However, the diagnosis and management of ETP-ALL is still challenging. There are limited choices of novel therapies so far. In this review article, it highlighted the diagnostic issue of ETP-ALL, pitfall in diagnosis, and strategy of accurate diagnosis. The review also summarized current understanding of molecular mechanism of leukemogenesis. The emerging role of risk-adapted therapy and allogenic stem cell transplant in optimizing the outcome of patients with ETP-ALL was discussed. Finally, some potential novel therapies were proposed based on the current understanding of molecular pathogenesis.

Highlights

T lymphoblastic leukemia (T-Acute Lymphoblastic Leukemia (ALL)) is an aggressive hematological malignancy, which accounts for 15% of pediatric ALL and 25% of adult ALL cases [1]
The rationale of the scoring system was that the frequency of CD2, surface CD3, CD4, and CD10 expression was much less frequent from the findings reported by Coustan-Smith et al [12] Zuurbier et al evaluated 117 patients with T-ALL and found that the genetic signature of Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) was best correlated with the following immunophenotype: CD1a-negative, CD4 and CD8-double negative, CD34-positive, and/or CD13/CD33-positive
A total of 47 pediatric T-ALL patients from the Children’s Oncology Group (COG) 09404 and the Dana–Farber Cancer Institute (DFCI) 00-01 study were included in a study, which showed that the absence of the biallelic T-cell receptor (TCR) gamma deletion was strongly associated with induction failure

Summary

INTRODUCTION

T lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy, which accounts for 15% of pediatric ALL and 25% of adult ALL cases [1]. Morita et al recruited 171 pediatric and adult patients with T-ALL or T lymphoblastic lymphoma (T-LBL) They found that the cases of ETP-ALL and near-ETP-ALL showed certain similarity in their genetic profile, except that myeloid-associated mutations were enriched in ETPALL. A recent study performed on mouse models introduced oncogenic mutations in early lympho-myeloid progenitors, but not in hematopoietic stem cells (HSCs) or multipotent progenitors, and resulted in the development of TALL with the ETP-ALL phenotype [28] The results of these studies demonstrated the cellular origin of ETP-ALL using an in vivo model, which was not inferred from the immunophenotypic and genomic profile of ETP-ALL.

Results of Studies Involving Pediatric Patients

47 ETP-ALL patients

Upregulation of NOXA in AML

CONCLUSION